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Pulmonary arterial hypertension (PAH) describes a rare, progressive vascular disease caused by the obstruction of pulmonary arterioles, typically resulting in right heart failure. Whilst PAH most often manifests in adulthood, paediatric disease is considered to be a distinct entity with increased morbidity and often an unexplained resistance to current therapies. Recent genetic studies have substantially increased our understanding of PAH pathogenesis, providing opportunities for molecular diagnosis and presymptomatic genetic testing in families. However, the genetic architecture of childhood-onset PAH remains relatively poorly characterised. We sought to investigate a previously unsolved paediatric cohort (n = 18) using whole exome sequencing to improve the molecular diagnosis of childhood-onset PAH. Through a targeted investigation of 26 candidate genes, we applied a rigorous variant filtering methodology to enrich for rare, likely pathogenic variants. This analysis led to the detection of novel PAH risk alleles in five genes, including the first identification of a heterozygous ATP13A3 mutation in childhood-onset disease. In addition, we provide the first independent validation of BMP10 and PDGFD as genetic risk factors for PAH. These data provide a molecular diagnosis in 28% of paediatric cases, reflecting the increased genetic burden in childhood-onset disease and highlighting the importance of next-generation sequencing approaches to diagnostic surveillance.

Background and AimNICE guidelines recommend universal testing of newly diagnosed colorectal and endometrial cancer for Lynch syndrome (LS), however there is strong evidence of variation in delivery of these guidelines by clinical services. In England, through 7 regional Genomics Medicine Service Alliances (GMSA), a transformation project aims to establish robust pathways to improve guideline compliance (https://www.norththamesglh.nhs.uk/national-gmsa-transformation-project-lynch-syndrome/).MethodA national oversight group was formed in May 2021, with membership drawn from 21 sub-regional Cancer Alliances (CA) and 7 GMSA, charities and other stakeholders. Each CA was tasked with identifying and supporting a responsible ‘Lynch syndrome champion’ within each local cancer team, and we performed a baseline survey to identify barriers to the testing pathway. Workforce training focused on overcoming barriers to testing, identification of eligible patients and mainstreamed constitutional gene testing. Training is delivered via online modules (https://rmpartners.nhs.uk/lynch-syndrome-early-diagnosis-pathway-colorectal-cancer/), workshops, and face-to-face peer-support and co-consultation. Data analysis is performed in conjunction with the National Disease Registration Service (NDRS), and includes clinicopathological data for all cancer patients diagnosed across England, including somatic and constitutional testing outcomes.ResultsBaseline data from NDRS and from the survey demonstrates that although cancer teams self-reported that 71% offer universal testing for LS, in 2019 only 41% of colorectal cancer patients received any form of index tumour ‘mismatch repair ‘(MMR) testing, data which is available on an open access dashboard ‘cancerstats2’. By late 2022 this figure has increased to colorectal and endometrial tumour mismatch repair testing on the Lynch testing pathway from 43% to 91% nationally for CRC (and from 19% to 89% for endometrial cancer), equally across all geographies in England. Lynch champions have been identified in 195 local cancer teams, and LS nurses appointed in each GMSA to support workforce development, along with regional expert networks. 66 new mainstreaming services have been developed within cancer teams, offering genetic testing locally without referral to clinical genetics services. Subgroups have been established in primary care, nursing, pathology, training, and to pilot testing in other Lynch-related tumour types. Each GMSA has identified LS patients diagnosed via their service, used to ascertain 6750 people with LS for a Nationally coordinated screening programme from 2023, and the development of a National LS Registry.ConclusionsThis ongoing transformational project is supported by high levels of engagement across stakeholders in England. Despite barriers, significant quality improvement has been implemented, facilitating systematic delivery of universal testing for LS nationally, with reduction in variation in care.